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Complementary and Alternative Medicine in the United States (2005)

Chapter: 9 Dietary Supplements

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Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
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9
Dietary Supplements

Dietary supplements have become a prominent part of American popular health culture, a fact attested to by the ready supply of supplements in pharmacies; chain stores such as Sam’s Club, Costco, and Walmart; supermarkets; and health food stores. Vendors advertise cut-rate prices for dietary supplements on the Internet. Since the 1960s, the prevalence of vitamin, mineral, and herbal product use has increased in the United States (Kessler et al., 2001). Today, dietary supplements comprise a major industry, responsible for $18.7 billion in sales in 2002 (Nutrition Business Journal, 2003). Herbal product use increased 380 percent between 1990 and 1997 (Eisenberg et al., 1998), and recent survey data indicate that 14 percent of Americans have taken an herbal product or supplement within the last week (Kaufman et al., 2002) and that 18.9 percent have taken one in the past year (Barnes et al., 2004). The use of dietary supplements is primarily self-initiated rather than practitioner based and presents unique regulatory, safety, and efficacy challenges to consumers, researchers, and practitioners. These challenges are an integral part of the committee’s charge to identify major scientific, policy, and practice issues related to complementary and alternative medicine (CAM) and are the focus of this chapter.

DIETARY SUPPLEMENT USE IN THE UNITED STATES

Kaufman and colleagues (2002) have described the patterns of medication use (for both prescription and nonprescription drugs) by the ambulatory adult population of the United States. Among their findings were the observations that (1) 40 percent of the population routinely used one or

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×

more vitamin or mineral supplements; (2) 14 percent of the population had taken herbals and supplements during the previous week; and (3) among prescription drug users, 16 percent also took an herbal or supplement. Tables 9-1 and 9-2 summarize data on the most common supplements consumed by the American public. One shift in supplement usage is instructive. The use of St. John’s wort declined significantly between 2000 and 2001. A plausible reason for this is the negative attention that this herbal medicine received in both scientific journals and the popular press (Piscitelli et al., 2000; Shelton et al., 2001). To the extent that this is true, it demonstrates that the American public is responsive to reports of adverse events and scientific evidence involving the safety and efficacy of supplements as well as product adulteration disseminated in the press. Market sensitivity to scientific reports as well as drug advertisements related to CAM therapies need to be further examined, as they have for conventional medicine.

The American public’s views on the federal regulation of dietary supplements are also instructive. Blendon et al. (2001) reported on Americans’ views on dietary supplements determined in multiple randomized surveys, each with a sample size of greater than 1,000, performed from 1996 to 1999. The investigators found that approximately half (48 percent) of all American adults surveyed reported that they regularly take some type of nonprescription vitamin or dietary or mineral supplement. One in six (16 to 18 percent) reported that they regularly use dietary supplements, such as echinacea, ginseng, amino acids, or nonprescription hormones. Respondents with higher levels of education reported greater use than those with

TABLE 9-1 Ten Most Commonly Used Vitamins/Minerals and Herbal Supplements

Vitamin or Mineral

Percent Use

Herbal Supplement

Percent Use

Multivitamin

26

Ginseng

3.3

Vitamin E

10

Gingko biloba

2.2

Vitamin C

9.1

Garlic

1.9

Calcium

8.7

Glucosamine

1.9

Magnesium

3.0

St. John’s wort

1.3

Zinc

2.2

Echinacea

1.3

Folic acid

2.2

Lecithin

1.1

Vitamin B12

2.1

Chondroitin

1.0

Vitamin D

1.9

Creatine

0.9

Vitamin A

1.8

Saw palmetto

0.9

Any vitamin or mineral

40

Any herbal supplement

14

SOURCE: Adapted from Kaufman et al. (2002).

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×

TABLE 9-2 Top-Selling U.S. Dietary Supplements

Vitamins and Mineralsa

$ Millionsa

Nonherbal Dietary Supplementsa

$ Millionsa

Herbal Supplementsb

$ Millionsb

Percent Change from January 2002 to January 2003b

Multivitamins

839

Glucosamine/chondroitin

288

Garlic

34.5

–1.5

Calcium

340

CoenzymeQ-10

41

Ginkgo biloba

32.9

–28.9

Vitamin C

230

Melatonin

31

Echinacea

32.4

–18.9

Vitamin B complex

90

Amino acids

21

Soy

28.2

+1.6

Vitamin B

82

Fish oil/omega-3 fatty acid

14

Saw palmetto

23.1

–7.1

Iron

57

DHEA

11

Ginseng

21.6

–30.6

Vitamins A and D

34

Acidophilus

11

St. John’s wort

14.9

–38.4

Zinc

28

Lecithin

10

Black cohosh

12.3

+27.4

Potassium

14

Gelatin

8

Cranberry

11.8

+13.0

Glucose

7

Valerian

8.1

–31.4

Shark cartilage

6

Milk thistle

7.7

+9.2

Evening primrose

6.0

+2.1

Kava kava

4.4

–52.9

Bilberry

3.3

–4.9

Grape seed

3.0

–24.1

Yohimbe

2.4

+12.3

Green tea

1.7

+1.0

Ginger

1.0

–9.8

Pycnogenol

0.9

–36.0

Aloe vera

0.5

+1.1

Multiple herbs

8.5

+27.1

All other herbs not listed above

33.7

–5.9

SOURCES: aEisenberg (2001); bBlumenthal (2003a).

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×

less education. Regular users were also more likely to be white and non-Hispanic. Americans older than age 45 years were more likely to use supplements regularly than those who were younger (44 and 24 percent, respectively). The investigators also reported that uninsured Americans were significantly more likely than those with insurance to use dietary supplements (21 and 15 percent, respectively). Of note, they comment that one of six parents (18 percent) reported that they give dietary supplements to their children.

Blendon and colleagues (2001) noted that a 1997 survey found that one-third (36 percent) of adults thought that there was a dietary supplement that could help them live longer. Overall, 85 percent of regular users reported that dietary supplements are good for people’s health and well-being. That proportion was lower for those who were not regular dietary supplement users. Regular users believed that dietary supplements could help with the treatment of a wide range of medical conditions. About half of regular users believed that supplements are helpful for people with colds (61 percent), arthritis (53 percent), depression (52 percent), and influenza (49 percent). Some regular users viewed dietary supplements as helpful in the treatment of cancer (35 percent) and HIV infection-related immunodeficiency syndromes (16 percent). Another study that the investigators identified found that 82 percent of Americans surveyed said that they would seriously consider trying alternative treatments such as herbal medicines if they were terminally ill.

Importantly, Blendon and colleagues (2001) also found that those who were regular users believed strongly in the usefulness of various dietary supplements, irrespective of the scientific evidence. When asked what they would do if a government agency said that the supplement that they used most often was ineffective, 71 percent of regular users reported that they would continue to use it. In a follow-up survey, respondents were asked what they would do if the Food and Drug Administration (FDA) specifically said that the supplement that they used most was ineffective to see if use of the FDA name versus an unknown government agency would alter the results. Specific mention of the FDA did not lead to different responses. Once again, two-thirds (67 percent) of regular users of dietary supplements said that they would continue to take the supplement.

Regular users had more confidence in the safety of these products than nonusers: the majority of regular users (53 percent) believed that people are “rarely or never” harmed by taking dietary supplements; in contrast, 51 percent of nonusers reported that people are “often or sometimes” harmed by these supplements (Blendon et al., 2001).

Blendon and colleagues (2001) also queried the respondents about their attitudes towards governmental regulation of dietary supplements. A substantial percentage of respondents were confused about the role that the

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×

government currently plays in regulating supplements. Slightly more than half (53 percent) were aware that supplements are not regulated by the government. One-third (35 percent) believed that supplements are currently regulated, and 12 percent reported that they did not know (Blendon et al., 2001). However, the investigators reported that even with this level of public confusion, a majority of respondents expressed support for increased government regulatory efforts to ensure that dietary supplements are not harmful and are pure, that doses are consistent, and that advertising claims are true (Blendon et al., 2001). Eighty-one percent of respondents supported giving FDA the authority to allow new supplements to be sold only if the safety of the supplements has been tested by FDA; 80 percent supported giving FDA the authority to remove dietary supplements from the market if they are proven to be unsafe. Despite the large percentage of people in support of greater regulation, Blendon et al. (2001) also note, “a substantial number of respondents were not prepared to be denied access to existing dietary supplements that have not been previously tested for safety.” Similar levels of support were found among those who were regular users and those who were not (Blendon et al., 2001). As such, the matter of federal regulation of dietary supplements is clearly one for which there is currently much confusion on the part of the American public.

REGULATION OF DIETARY SUPPLEMENTS

Dietary Supplement Health and Education Act

The capstone of herbal medicine regulation is the Dietary Supplement Health and Education Act of 1994 (DSHEA, 1994). As seen from the survey data presented above, dietary supplements encompass many products, including herbs, vitamins, and minerals. DSHEA formally defined dietary supplements as

a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients:

  • a vitamin;

  • a mineral;

  • an herb or other botanical;

  • an amino acid;

  • a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or

  • a concentrate, metabolite, constituent, extract, or combination of any ingredient described above.

Dietary supplements are further defined as products that are labeled as dietary supplements and are not represented for use as a conventional

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×

food or as a sole item of a meal or the diet. Supplements can be marketed for ingestion in a variety of dosage forms including capsule, powder, softgel, gelcap, tablet, liquid, or indeed, any other form so long as they are not represented as conventional foods or as sole items of a meal or of the diet. (DSHEA, 1994)

DSHEA had enormous consumer support as evidenced by the approximately 2 million letters sent to members of the U.S. Congress in support the act (Soller, 2000). The legislation sought to be responsive to the public and was passed in the spirit of improving the health of Americans and empowering consumers to make their own choices about preventive health care practices. In doing so, however, DSHEA designated that supplements be regulated similarly to foods. This crucial distinction exempted manufacturers from conducting premarket safety and efficacy research and eliminated FDA’s premarket regulatory authority. Before DSHEA, FDA attempted to regulate dietary supplements as foods evaluating the safety of all new ingredients, including those used in dietary supplements. DSHEA eliminated this requirement, and as a result, the dietary ingredients used in dietary supplements are no longer subject to the premarket safety evaluations required of other new food ingredients or for new uses of old food ingredients. They must, however, meet the requirements of other safety provisions (FDA, 1995). Table 9-3 shows how dietary supplements are regulated in comparison to foods and drugs.

The establishment of dietary supplements as foods limited FDA’s premarketing regulatory authority and placed FDA in a reactive, postmarketing role. If FDA can prove that a supplement presents a significant or unreasonable risk of injury or illness when it is used as recommended on the label, it may remove a product from the market. This occurred in 2004, when FDA prohibited the sale of dietary supplements containing ephedrine alkaloids. To substantiate its ruling, FDA conducted a risk-benefit analysis of ephedra and examined evidence from the known pharmacology of ephedrine alkaloids, the peer-reviewed literature on effects of ephedrine alkaloids, and reported adverse events after consumption of the product. Review “showed little evidence of ephedra’s effectiveness except for short-term weight loss, while confirming that the substance raises blood pressure and stresses the heart” (http://nccam.nih.gov/health/alerts/ephedra/consumeradvisory.htm). FDA determined that data did not indicate a health benefit sufficient to outweigh the short- and long-term risks of use (e.g., increased blood pressure, and heart rate) (FDA, 2004). Adverse event analysis is complicated by the fact that supplement manufacturers are not required to report adverse events.

DSHEA authorized FDA to establish good manufacturing practice regulations specific to dietary supplements, and these are in development (FDA, 2003a). However, until these practices are implemented, manufacturers are

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×

TABLE 9-3 FDA Regulation of Foods, Drugs, and Dietary Supplements

Status

Dietary Supplements

Foodsa

Food Additives

New Drugsb

Premarket approval required

Noc

Nod

Yes

Yes

Risk-benefit analysis conducted by FDA before marketingNo

No

No

Yes

 

Postmarketing reporting or surveillance by industry required

No

No

Rarely

Yes

Burden of proof for demonstrating safety or lack thereof

FDA

FDA

Manufacturer

Manufacturer

aFoods (including conventional foods and dietary supplements), unlike drugs, are considered safe (reasonable certainty of no har m), and thus risk-benefit analysis is not applicable.

bThis description applies to“new” drugs. Many over-the-counter drugs are regulated under FDA’s Over-The-Counter Drug Review procedures, which do not provide for postmarketing surveillance.

cA 75-day premarketing notification, but not premarketing approval, is required for dietary supplements containing ingredients n ot marketed before 1994.

dIn 2001, FDA proposed a rule requiring marketers of food developed through biotechnology to notify the agency at least 120 days before commercial distribution and to provide information to demonstrate that the product is as safe as its conventional counterpart (FDA, 2001).

SOURCE: Adapted from IOM (2005).

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×

accountable to consumers only on the basis that they have made a good faith effort to ensure that their products contain pure substances and are not contaminated, weakened, or mislabeled.

Dietary Supplement Labels

DSHEA also included labeling guidelines for supplements and prohibited products from containing information on the label that claims that the product can treat or cure a disease. Three categories of claims for food and dietary supplement labels are allowed: (1) health claims, (2) structure-function claims, and (3) nutrient content claims. Table 9-4 provides examples of each type of claim.

Health Claims

Health claims can be established by three methods: (1) authorization by FDA after a careful review of the scientific literature, (2) an authoritative

TABLE 9-4 Label Claims for Dietary Supplements

Health Claim

Structure-Function Claim

Unallowable Disease Claim

Nutrient Content Claim or Percentage Claim

Regular exercise and a healthy diet with enough calcium helps teens and young adult white and Asian women maintain good bone health and may reduce their high risk of osteoporosis later in life.

Supports the immune system

Supports the body’s ability to resist infection

Excellent source of choline; contains 55 mg of choline per serving, which is 10 percent of the daily value for choline (550 mg)

Healthful diets with adequate folate may reduce a woman’s risk of having a child with a brain or a spinal cord defect.

Maintains healthy lung function

Protective against the development of cancer

More, added, extra vitamin C

Some scientific evidence suggests that consumption of antioxidant vitamins may reduce the risk of certain forms of cancer. However, FDA has determined that this evidence is limited and not conclusive.

Helps promote digestion

Promotes low blood pressure

 

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×

statement of a scientific body of the U.S. government or National Academy of Sciences,1 or (3) the results of the 1999 Pearson v. Shalala court decision (FDA, 2003b). The Pearson case challenged FDA’s denial of four health claims: dietary fiber may reduce the risk of colorectal cancer, antioxidant vitamins may reduce the risk of certain cancers, omega-3 fatty acids may reduce the risk of coronary heart disease, and 0.8 milligram (mg) of folic acid in dietary supplement form is more effective than a smaller amount obtained through foods for reducing neural tube defects. The final decision stated that FDA could not “reject health claims that the agency determines to be potentially misleading unless the agency also reasonably determines that no disclaimer would eliminate the potential deception” (FDA, 1999). The court also called for FDA to clarify the meaning of the “significant scientific agreement” standard.

Most health claims are applicable only to foods, for example, “low-fat diets rich in fiber-containing grain products, fruits, and vegetables may reduce the risk of some types of cancer, a disease associated with many factors.” However, two health claims for dietary supplements have been approved: folate reduces the risk of neural tube defects, and calcium reduces the risk of osteoporosis (FDA, 2000).

Structure-Function Claims

The second category created by DSHEA for foods and dietary supplements labels is structure-function claims. Such claims may only contain statements about how a product affects maintenance of normal functioning or describe general well-being because of the “consumption of a nutrient or dietary ingredient.” Structure-function claims may also describe the means by which a nutrient or dietary ingredient acts to maintain a particular structure or function. Examples include “calcium builds strong bones” and “fiber maintains bowel regularity.” Because manufacturers are responsible for the truthfulness and accuracies of these claims, if a product label contains a structure-function claim, it must also include the disclaimer, “This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.” An additional requirement of structure-function claims is that FDA must be notified of the claim within 30 days after such a product is marketed.

1  

At present, this method of oversight for health claims cannot be used for dietary supplements, as Congress did not include dietary supplements in the provisions for health claims based on authoritative statements.

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×
Nutrient Content Claims

The final category of product labels is nutrient content claims. These claims describe the level of a nutrient or dietary substance in a product, using terms such as “good source,” “high,” or “free.” With few exceptions, nutrient claims may be used only for nutrients or dietary substances that have an established daily value, such as fat, cholesterol, calories, and sodium. However, since many dietary ingredients, including most dietary supplements, lack established or recommended daily intake values, a subcategory called percentage claims also exists. These claims describe the percentage of a product, such as “40 percent omega-3 fatty acids” or make a comparative percentage claim, such as “twice the omega-3 fatty acids per capsule (80 mg) as in 100 mg of manhaden oil (40 mg)” (FDA, 2003b).

Off-Label Use of Dietary Supplements

For the majority of dietary supplements, particularly herbal products, inadequate evidence exists to qualify them for health or nutrient content claims. Consequently, many dietary supplements are subject to structure-function claims. However, despite all the attention given to proper labeling, recent survey data and clinical trials indicate that dietary supplements are not being used according to label claims (Blendon et al., 2001; Kaufman et al., 2002). Instead, many supplements are being taken for specific health concerns and health promotion, even though the effectiveness of the supplements has not yet been demonstrated. In response to this problem, several research efforts have been launched to evaluate the efficacies of supplements for off-label health uses, for example:

  • Echinacea and colds (Grimm and Muller, 1999; Turner et al., 2000)

    Hypericum perforatum (St. John’s wort) and major depressive disorder (Hypericum Depression Trial Study Group, 2002; Shelton et al., 2001)

  • Black cohosh and red clover for the relief of menopausal symptoms (ongoing National Center for Complementary and Alternative Medicine [NCCAM]-funded study at the University of Illinois, Chicago)

  • Effects of garlic on cholesterol (ongoing NCCAM-funded study at Stanford University)

  • Glucosamine, chondroitin sulfate, and the combination of glucosamine and chondroitin sulfate for knee pain associated with osteoarthritis (ongoing multisite NCCAM-funded study)

  • Chelation with EDTA (ethylenediaminetetraacetic acid) to treat heart disease (ongoing multisite NCCAM-funded study)

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×

Federal Trade Commission

In addition to FDA’s responsibilities for ensuring safety, the Federal Trade Commission (FTC) regulates product advertising. For all products, FTC maintains two guiding principles: (1) advertising must be truthful and not misleading, and (2) before an advertisement is disseminated, all objective product claims must be adequately substantiated (FTC, 2001).

In accordance with its goal of ensuring that consumers receive accurate information about dietary supplements so that they may make informed decisions about the use of products, FTC released Dietary Supplements: An Advertising Guide for Industry (FTC, 2001). The guidelines are intended to clarify how FTC policies and enforcement practices relate to dietary supplement-related advertising. In addition to FTC’s standard substantiation requirements, the document outlines the type of evidence needed to support both expert endorsements and claims based on traditional use, as well as appropriate use of the DSHEA disclaimer and third-party literature.

In addition to the guidance document, FTC launched Operation Cure. Although the campaign is not limited to dietary supplements, it aims to enforce FTC regulations and educate consumers on recognizing health fraud. However, as evident in the literature (Bonakdar, 2002; Morris and Avorn, 2003) and acknowledged by Howard Beales, director of FTC’s Bureau of Consumer Protection, “unfounded and exaggerated claims for dietary supplements have proliferated,” and the FTC has partnered with FDA to increase its enforcement activities (Beales, 2003).

Dietary Supplement Regulation Outside of the United States

The use of herbal products is prevalent throughout the world (WHO, 2002), and several countries have been addressing the use and regulation of dietary supplements for many years, whereas others like the United States are in the early years of their regulatory efforts.

Canada

New Natural Health Products (NHP) regulations came into effect in Canada on January 1, 2004. The intent of the regulations is to “ensure a balance between Canadians’ freedom of choice with respect to natural health products and the assurance of consumer safety” (HealthCanada, 2003). The regulations establish NHPs as a subset of drugs. Before the establishment of the regulations, NHPs could be sold as either foods or drugs, depending on whether a health or therapeutic claim was made. In

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×

developing the regulations, Health Canada decided that because NHPs are taken for therapeutic reasons rather than caloric purposes or to address hunger, they are more similar to drugs than foods.

The NHP regulations authorize the following regulatory oversight: (1) a premarketing review and approval for safety, efficacy, claims, and product specification; (2) adherence to good manufacturing practice (GMP) requirements for manufacturing, packaging, and labeling; (3) requirement for a site license where any regulated activity is conducted; (4) regulatory oversight for a clinical trial process; and (5) a postmarketing surveillance program for adverse reactions (Taller, 2003). The regulations call for a 6-year transition period. By the end of 2 years, all manufacturers, importers, packagers, and labelers will use GMPs and have site licenses, and by the end of 6 years, all NHPs will be identified with either a natural product number (NPN) or a drug identification number for homeopathic medicine (DIN-HM). Product labels will include a complete list of ingredients, conditions for use, a health claim when appropriate, a lot number, and the manufacturer’s contact information.

Germany

Since 1976 Germany has defined herbal medicines as medicinal products and required premarketing approval of their quality, safety, and efficacy. In addition, herbal medicinal products must contain only plant material in crude or processed form and may have a therapeutic or prophylactic claim. The same manufacturing standards, as well as labeling and advertising regulations, pertain to both herbal and medicinal products (i.e., the products must be reproducible and nontoxic) (Richter, 2003b). The safety, efficacy, and quality of herbal products were determined by Germany’s Second Medicines Act of 1978. The act required a scientific review of all medicines in the pharmaceutical market, including conventional drugs as well as medicinal plants. Several commissions were established, and Commission E was charged with reviewing botanical drugs and preparations from medicinal plants. Commission E completed the monographs in 1994, and the American Botanical Council published the monographs in English (Levy, 1998).

The stated objective of Commission E was to ensure that approved botanicals are reasonably safe when they are used according to the label instructions and to remove unapproved botanicals from the market, even if they pose only minor safety risks (Blumenthal et al., 1998). For the Commission E reviews, it was the manufacturer’s responsibility to provide proof of quality, and the commission assessed the scientific literature on safety and effectiveness. Herbal products were assigned one of three approval ratings: (1) positive (approved), (2) negative (unapproved), or (3) negative-

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×

null (unapproved). The potential therapeutic benefit was a factor in making the ratings.

France

As in Germany, France also regulates herbal products that are intended for medicinal use as drugs. All medicinal products, including herbals, require premarketing approval, and the manufacturer bears the responsibility of proving quality, safety, and efficacy. An abridged approval process is available for herbal products with a history of traditional use. For these products, the pharmacologic, toxicologic, and clinical data are evaluated, in addition to information on safety, risks-benefits, and well-established use for self-medication. Products approved through the abridged process are limited to making a claim on the label, such as “Traditionally used in _______” rather than a disease claim (Richter, 2003b).

Compared with the regulatory frameworks adopted in these industrialized countries, it is clear the United States has developed a unique regulatory system for dietary supplements. Unlike Canada, Germany, and France, the United States regulates dietary supplements similarly to foods, and does not require premarketing approval of safety, nor does the burden of proof rest on the manufacturer.

PRODUCT QUALITY AND SAFETY

As described above, many Americans are uncertain whether dietary supplements are subject to safety and efficacy evaluations similar to those used for over-the-counter medications (Blendon et al., 2001). In the same survey, the majority of respondents also believed that there was “not enough regulation” to ensure that supplements are not harmful (59 percent), to ensure that supplements are pure and contain consistent doses (60 percent), and to confirm that advertising claims are true (64 percent).

At present, there is a lack of quality control for dietary supplements which is troubling because an adulterated product could compromise that product’s safety. One report noted that 32 percent of Asian patent medicines were found to contain undeclared pharmaceuticals or heavy metals; 10 to 15 percent contained lead, mercury, or arsenic (Marcus and Grollman, 2002). Also, the herbal product PC-SPES (used by thousands for the treatment of advanced prostate cancer) was found to be contaminated with diethylstilbestrol and warfarin (Straus, 2002). In a recent article, De Smet (2002) recommends that data on the manufacturer, product composition, storage, and indications for use be maintained to ensure the quality of dietary supplements. The manufacture of a consistent product, a process often referred to as “standardization,” is another component of product

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×

quality. Standardization of dietary supplements is challenging, however, because herbal products contain a mixture of chemically active components, and the primary active component is often unknown. This lack of consistency affects both researchers and consumers, as neither can be ensured of a reliable product.

One approach implemented by several supplement manufacturers is a “seed-to-shelf” philosophy of quality control. This approach enacts standards for each step of the manufacturing process: from the use of pure starting products to growth, harvest, extraction, and screening for impurities. In addition to setting such standards, quality tests are also performed at each step of the process (Dentali, 2003; Morrison, 2003).

Good Manufacturing Processes

One effort to improve the quality of dietary supplements is currently in development. In March 2003, FDA released draft standards for current GMPs (cGMPs) for dietary supplements. The cGMPs will require standards in the manufacturing, packing, and holding of dietary supplements to reduce the risk of contamination with pesticides, heavy metals, and other impurities. A lack of GMPs contributes to problems with standardization. For example, Gilroy et al. (2003) conducted a study to assess the contents of preparations containing only echinacea. They found that of the 59 separate samples purchased in the Denver, Colorado area, 10 percent contained no measurable echinacea. Proposed cGMPs would ensure proper labeling of a dietary supplement’s identity, purity, quality, strength, and composition (FDA, 2003a). The goal of cGMPs is to develop more consistent products, but they do not address safety, efficacy, or cost-effectiveness compared with those of existing prescription or over-the-counter drugs. Standards will be established by the individual manufacturers, which will increase product consistency within a company but not within the industry (Betz, 2003). For example, Company A will now produce a consistent St. John’s wort product, but it may not be consistent with or comparable to the St. John’s wort manufactured by Company B. Furthermore, GMPs will likely not solve the fundamental issues regarding the need for consistent products and quality assurance.

Reactions to the cGMPs are varied. Although many acknowledge that the cGMPs should yield higher consumer confidence in herbal products, many are concerned that the proposed cGMPs are strongly based on a pharmaceutical model and the implementation of such practices will have prohibitive costs (Blumenthal, 2003b). Blumenthal notes that industry and FDA have reached a general consensus that many smaller to medium-size manufacturers will not be able to meet the requirements and will be put out of business.

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
×

Assessing Product Safety and Quality

Because research on the efficacies of herbal products requires consistent products, NCCAM recently established a policy on the quality of natural products to provide guidance for researchers seeking NCCAM funding (NCCAM, 2003). The policies are intended to help researchers identify and use products of sufficient quality for their investigations. NCCAM recommends that the natural products used in a study be described in sufficient detail and that the results be understood and independently reproduced. Studies must prove that the test material has been reliably identified, and the content should be described by analysis of putative active ingredients and by chromatographic analysis of the whole material by the commercial company or independent laboratory. Also, depending on the study design, verification of the samples at the start and end of the study may be necessary to ensure product stability (NCCAM, 2003).

With the lack of federal standards for dietary supplements, several organizations have initiated efforts to improve and test the safety, quality, and efficacy of supplements. The following overview focuses on approaches taken by organization- or government-sponsored committees or a peer-reviewed process.2 The list should not be considered inclusive of all efforts to consider safety, efficacy, or quality of dietary supplements, nor should it be considered committee endorsement of the approaches used.

The Agency for Healthcare Research and Quality (AHRQ) of the U.S. Department of Health and Human Services is authorized to sponsor, conduct, and disseminate research to improve the quality and effectiveness of health care. AHRQ administers evidence-based practice centers (EPCs), which have produced reports on the effectiveness and safety of a limited number of dietary supplements requested by other federal agencies. The EPC reports are based on a systematic analysis of the relevant scientific data and are designed to differentiate the types and strengths of a comprehensive body of evidence.

Nominations for clinical topics to be reviewed by an EPC are solicited through notices in the Federal Register. Topics must meet specific selection criteria, including high incidence; significance for the needs of users of Medicare, Medicaid, or other federal health programs; high cost; controversy about effectiveness; and availability of scientific data. On the basis of this process, reports on six dietary supplements3 have been reviewed as of October 2003.

2  

A comprehensive discussion of these private and public safety assessments is available in Dietary Supplements: A Framework for Evaluating Safety (IOM, 2005).

3  

The topics of the six reports are: Antioxidant supplements for prevention and treatment of cancer (October 2003); Antioxidant supplements for prevention and treatment of cardio-

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
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The American Herbal Pharmacopoeia (AHP), a nonprofit organization, develops monographs on the quality, effectiveness, and safety of botanical products commonly used in the United States. The monographs are intended to provide consumers, health care professionals, and botanical manufacturers with the knowledge required to use and manufacture botanical products safely and effectively and to provide regulatory bodies and researchers with guidance on the integration of botanical products into the health care system (AHP, 2004a).

Botanicals are selected for review and description in a monograph on the basis of the extent of use, the unique value of the botanical, and sponsorship by other interested organizations or companies (AHP, 2004a). The monographs are relatively detailed compared with the monographs produced by other organizations and are released as they are completed. Eighteen monographs have been published4 since 1994, and 7 more have been proposed.

The American Herbal Products Association (AHPA) is a national trade association for the botanical products industry. AHPA reviewed safety data for 600 herbs and published the information in the American Herbal Products Associations’ Botanical Safety Handbook (McGuffin et al., 1997). The publication assigned botanicals to one of four safety classes. Class 1 contains botanicals that AHPA believes can be used safely when they are used appropriately. Class 2 contains botanicals for which certain restrictions apply (e.g., external use only and not recommended for use during pregnancy). Class 3 contains botanicals for which significant data exist to recommend special labeling. Class 4 contains botanicals for which AHPA found insufficient data for classification.

The Natural Medicines Comprehensive Database (NMCD) is a private effort and was first published in 1999 by the Therapeutic Research Center. It is designed to bring together the consensus of the available data on natural medicines so that practitioners do not need to search multiple sources to find scientifically reliable and clinically practical information on botanical medicines and supplements for their patients. Products are evaluated on the basis of several factors: safety, effectiveness, mechanism of

   

vascular disease (CVD) (July 2003); Ephedra and ephedrine for weight loss and athletic performance enhancement (March 2003); S-adenosyl-L-methionine (SAMe) for depression, osteoarthritis, and liver disease (August 2002); Garlic and CVD (October 2000); and Milk thistle effects (September 2000).

4  

The monographs published by AHP covered astragalus root, hawthorn berry, hawthorn leaf and flower, schisandra berry, valerian root, willow bark, ashwaganda root, black haw, chaste tree, cramp bark, goldenseal root, reishi mushroom, bilberry fruit, cranberry fruit, dang gui root, garlic powder, ginkgo leaf, black cohosh (AHP, 2004b).

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
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action and active ingredients, adverse reactions, interactions, drug influences on nutrient levels and depletion, and dosage and administration (NMCD, 1999).

Natural Standard was founded by clinicians and researchers as a multi-institution initiative in January 2000 to provide evidence-based information about CAM therapies (Natural Standard, 2004). The organization is a private, independent service that is not supported by any interest group, professional organization, or pharmaceutical manufacturer. Each monograph assigns a letter grade (A to F) pertaining to the level of evidence of effectiveness for specific indications. Information on safety, toxicology, precautions, contraindications, interactions, and mechanism of action is also provided; but these do not contribute to the letter grade.

In 1998 the Physician’s Desk Reference (PDR) organization, a private, for-profit group, expanded its publications to include a PDR for Herbal Medicines. The second edition was published in 2000 and contains monographs on approximately 700 herbs. Of the 700 monographs, 300 are based on the German Commission E monographs. The monographs contain information on efficacy, safety, potential interactions, effects, contra-indications, precautions, adverse reactions, and dosage. In addition, PDR published a reference volume for nonprescription drugs and dietary supplements in 2003 and a PDR for nutritional supplements in 2001.

The World Health Organization (WHO) has undertaken several efforts related to the safety, efficacy, and quality control of herbal medicines and has published three volumes of monographs since 1999, with a fourth volume in development. Each volume contains approximately 30 monographs. For each medicinal plant, information is included about purity tests, chemical constituents, uses, clinical studies, pharmacology, contraindications, warnings, precautions, adverse reactions, and posology (i.e., pharmacological determination of appropriate doses of drugs and medicines). In addition, in 2004 WHO published Guidelines on Good Agricultural and Collection Practices for Medicinal Plants, as well as several other reports related to quality control, appropriate use, and regulations pertaining to herbal medicines.

The U.S. Pharmacopeia-National Formulary (USP-NF), a non-government, nonprofit organization, develops and provides standards of identity, strength, quality, purity, packaging, and labeling of drugs sold in the United States. However, unlike the previously discussed monographs, USP-NF standards do not evaluate safety. Their standards were recognized by the U.S. Congress in the Federal Food, Drug, and Cosmetic Act of 1938 as the official compendium of the United States, making its established standards for drugs essentially similar to federal regulations.

As a separate effort, USP-NF also developed the Dietary Supplement Verification Program (DSVP) in November 2001. DSVP is designed to

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
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ensure that dietary supplement products contain the declared ingredients in the declared quantities. USP collaborates with manufacturers who voluntarily submit their products for testing. The USP certification award is granted if the product meets five quality standards: (1) contains the ingredients stated on the label; (2) has the declared amount of ingredients; (3) will disintegrate or dissolve effectively to release nutrients for absorption into the body; (4) has been screened for harmful contaminants such as pesticides, bacteria, and heavy metals; and (5) has been manufactured by safe, sanitary, and well-controlled procedures. In addition, USP performs an initial screening so that products with known safety concerns are not certified and conducts random tests of marketed products carrying the mark for the USP certification award to ensure that they continue to meet USP standards over time.

SAFETY

Under the current DSHEA legislation, supplements are not subject to the same safety precautions as prescription and over-the-counter medications. Instead of premarketing testing, FDA must prove that a supplement is unsafe to remove it from the market. For medications, manufacturers are required to comply with the Federal Food, Drug, and Cosmetic Act and ensure the safety of their products before marketing. For new dietary supplement ingredients (those not marketed before the passage of DSHEA), before marketing manufacturers must provide FDA with the information that forms the basis on which the manufacturer has concluded that the product is safe. Although many supplement manufacturers recognize that the industry can be sustained only if they market safe products that perform in accordance with their claims (Young, 2000), product inconsistency has been demonstrated for several herbs (Gilroy et al., 2003; Raloff, 2003).

De Smet (2002) identified three safety concerns: adverse effects of the herb, drug-herb interactions, and an indirect risk of delaying or replacing conventional treatment with treatment with an herb with unestablished efficacy. Even though they are natural products, herbs contain biological and chemical properties that may lead to rare, acute, or chronic adverse effects. Drug-herb interactions also present a potential risk to many consumers, given that one in six people take prescription or over-the-counter medications and dietary supplements concurrently (Kaufman et al., 2002). The interactions of a popular herb, St. John’s wort, with cyclosporine, indinavir, nevirapine, oral contraceptives, and amitriptyline have been reviewed in the literature (Ioannides, 2002).

To address the question of product safety, the FDA recently asked the Institute of Medicine (IOM) to develop a framework for evaluating the safety of dietary supplement ingredients. The framework was published in

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
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2005 and includes a process for evaluating and describing the available information to establish the risk of harm and science-based principles to serve as guidance for evaluating the risk to human health (IOM, 2005).

The IOM framework suggests a three-step process for determining the risk of harm. Because FDA evaluation of every dietary supplement ingredient is unrealistic, the first step of the framework relies on “signal detection” to indicate that there may be a safety concern warranting further examination. If a signal is found, the second step is to conduct a review of the available information, such as the quality of the adverse event report, its applicability to humans, or the route of exposure. In addition to reviewing this information, it may be feasible to collect information to place the signal in context. If a safety concern remains after completion of this initial review, IOM recommended the performance of an integrative evaluation consisting of an in-depth literature search and review, drafting of a safety monograph, integration of the data into an analysis to complete the monograph, and possibly, referral of the monograph to an advisory body for additional input before FDA decides whether to take regulatory action. If the integrative evaluation results in a lower level of concern, FDA should continue to monitor the supplement for safety concerns through ongoing assessments of the literature. This responsibility rests on FDA, because DSHEA does not require postmarketing surveillance.

The committee supports several of the conclusions and recommendations in the IOM framework that address the legal and regulatory barriers affecting FDA’s ability to protect the health of the public:

It is very challenging to carry out the mandate of DSHEA given the limitations it imposes on the quantity and quality of the currently available scientific data related to the safety of dietary supplement ingredients … In line with these findings, members of the scientific and medical community have strongly advised that the regulatory mechanisms for monitoring the safety of dietary supplements, as currently defined by DSHEA, be revised. The constraints imposed on the FDA with regard to ensuring the absence of unreasonable risk associated with the use of dietary supplements make it difficult for the health of the American public to be adequately protected. (IOM, 2005)

An additional conclusion from the 2005 framework report states, “DSHEA should be amended to require that a manufacturer and distributor report to the FDA, in a timely manner, any serious adverse event associated with use of its marketed product of which the manufacturer or distributor is aware” (IOM, 2005).

Both the IOM framework and a recent review on the quality of dietary supplement reference books (Chambliss et al., 2002) conclude there is a wide variation among references, and multiple sources should be consulted to obtain the most comprehensive information about product safety and

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
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quality. This uncertainty about safety, the lack of premarketing safety data, and the proliferation of misleading and unfounded claims about dietary supplements place researchers, consumers, and conventional medical practitioners in a unique situation. It is a challenge to guide and advise patients about their use of supplements in the absence of evidence on their safety, quality, efficacy, and cost-effectiveness. Only when products are consistently manufactured, characterized, and evaluated for safety and efficacy will physicians be able to judiciously advise their patients about their use.

RESEARCH ON DIETARY SUPPLEMENTS

Office of Dietary Supplements

Another component of DSHEA established the Office of Dietary Supplements (ODS) within the National Institutes of Health to promote, conduct, and coordinate scientific studies on dietary supplements. As discussed in Chapter 1, the ODS 2004–2009 Strategic Plan sets five overarching goals related to research, information communication, and education. To achieve these goals, ODS plans to place greater emphasis on the use of emerging technologies, cross-disciplinary studies, training and education of investigators, translation of research, and establishment of a process for regular evaluation of ODS programs and activities.

In the last 5 years, ODS has initiated many efforts to improve the quality of dietary supplement research. It established a program to improve analytical methodologies and develop standard reference preparations of dietary supplements and has created two databases that are publicly accessible: the Computer Access to Research on Dietary Supplements (CARDS) database and the International Bibliographic Information on Dietary Supplements (IBIDS) database. The CARDS database currently contains information on federally funded dietary supplement research and is continually updated. The IBIDS database provides access to bibliographic citations and abstracts from the published international scientific literature on dietary supplements. An additional resource for the research community and the public is evidence-based review reports, commissioned through a partnership with NCCAM from AHRQ’s EPCs.

Another instance of ODS partnerships involves NCCAM, the National Institute for Environmental Health Sciences, the Office of Research on Women’s Health, and the National Institute of General Medical Sciences. Together, they fund six Centers for Dietary Supplement Research. The centers emphasize botanicals and aim to identify and characterize botanicals, assess their bioavailabilities and activities, explore their mechanisms of action, conduct preclinical and clinical evaluations, establish training and

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
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career development, and help select the botanicals to be tested in clinical trials.

NCCAM Research Efforts

As part of its effort to understand which CAM therapies work and which ones are safe, NCCAM supports research on herbal products. Recently, NCCAM noted that much of its research portfolio was devoted to clinical trials and in the future, it plans to place greater emphasis on studies that will help provide an understanding of the mechanisms of CAM modalities. It is hoped that such research will aid with the acceptance of CAM therapies by conventional medicine, as well as clarify research markers and design questions. For dietary supplements in particular, NCCAM notes that poorly characterized products and unknown optimal dosage schedules may cause premature efficacy studies to fail and may limit further research. Therefore, NCCAM is interested in determining “active ingredients, dosing, pharmacology, stability, and bioavailability; to identify surrogate markers; and to assess study feasibility” (NCCAM, 2003). The committee believes that more preclinical and clinical trials on dietary supplements are needed and that it is crucial for the products being evaluated to adhere to a seed-to-shelf quality control system.

NCCAM supports five Centers for Dietary Supplement Research, which are located at Purdue University, the University of Illinois at Chicago, the University of California at Los Angeles, the University of Arizona, and the University of Missouri-Columbia. Each center has a unique focus: age-related diseases, women’s health, botanicals, phytomedicines, and phytonutrients, respectively. Examples of ongoing NCCAM-funded research include interactions between olive leaf extract and anti-HIV drugs, phytoestrogens for multiple sclerosis, ginger for chemotherapy-induced nausea and emesis, Ginko biloba and vascular function, and herb-drug interactions. Research abstracts for all research funded by the National Institutes of Health are available through an online database, CRISP (Computer Retrieval of Information on Scientific Projects [http://crisp.cit.nih.gov/]).

Research Needs and Disincentives

Reliable products are necessary to conduct quality research, and at present, most herbal supplements are not available in reliable or consistent forms. As stated above, unlike prescription drugs and over-the-counter medicines, manufacturers of dietary supplements are not required to test their products for safety or efficacy. In addition to this missing legal requirement, there is a financial disincentive for such research. Because dietary supplements are ineligible for patent protection, manufacturers have a

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
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financial disincentive to invest in research on these products. Without patent protection and an ensuing period of exclusivity, a manufacturer’s results would be publicly available for use by its competitors, thus jeopardizing the manufacturer’s ability to regain the money invested in safety and efficacy testing (Richter, 2003a).

Despite this disincentive, research on the efficacy of dietary supplements is crucial, and for future studies to be most useful, dietary supplements should be evaluated in comparison with conventional medicines and the studies must use well-characterized products. Even when a reliable product is used, there is still a challenge in synthesizing the research results and performing meta-analyses, given the multiple brands and product characteristics. Future product reviews that identify safe and effective herbs and that stratify the research results by brand or manufacturer would add meaning and value.

CONCLUSIONS AND RECOMMENDATIONS

The committee is concerned about the quality of dietary supplements in the United States. There is little product reliability (Raloff, 2003), and because patent protection is not available for natural products, there is little incentive for manufacturers to invest resources in improving product standardization. In addition to the confusion that this introduces to consumers, the lack of reliable and consistent products is a challenge to the research and clinical practice communities. Without consistent products, research is extremely difficult to conduct or generalize. Furthermore, without high-quality research, evidence-based clinical recommendations cannot be made to guide patients.

As a result of their pharmacological properties, dietary supplements, particularly botanical products, carry a risk of adverse effects and interactions. Unlike vitamins and minerals, herbal supplements are composed of many active compounds, and often, the primary active ingredient is unknown. Without knowing the active ingredient(s), it is a challenge for manufacturers to set standards that bear any therapeutic meaning. As such, consistency and quality checks throughout the manufacturing process garner even more importance (Berman and Straus, 2004).

To improve product consistency and reliability, the committee recommends that the U.S. Congress and federal agencies, in consultation with industry, research scientists, consumers, and other stakeholders, amend the Dietary Supplement Health and Education Act of 1994 and the current regulatory scheme for dietary supplements, with emphasis on strengthening:

  • Seed-to-shelf quality control,

  • Accuracy and comprehensiveness in labeling and other disclosures,

  • Enforcement efforts against inaccurate and misleading claims,

Suggested Citation:"9 Dietary Supplements." Institute of Medicine. 2005. Complementary and Alternative Medicine in the United States. Washington, DC: The National Academies Press. doi: 10.17226/11182.
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  • Research into how consumers use supplements,

  • Incentives for privately funded research into the efficacies of products and brands, and

  • Consumer protection against all potential hazards.

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Next: 10 Conclusion »
Complementary and Alternative Medicine in the United States Get This Book
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Integration of complementary and alternative medicine therapies (CAM) with conventional medicine is occurring in hospitals and physicians offices, health maintenance organizations (HMOs) are covering CAM therapies, insurance coverage for CAM is increasing, and integrative medicine centers and clinics are being established, many with close ties to medical schools and teaching hospitals. In determining what care to provide, the goal should be comprehensive care that uses the best scientific evidence available regarding benefits and harm, encourages a focus on healing, recognizes the importance of compassion and caring, emphasizes the centrality of relationship-based care, encourages patients to share in decision making about therapeutic options, and promotes choices in care that can include complementary therapies where appropriate.

Numerous approaches to delivering integrative medicine have evolved. Complementary and Alternative Medicine in the United States identifies an urgent need for health systems research that focuses on identifying the elements of these models, the outcomes of care delivered in these models, and whether these models are cost-effective when compared to conventional practice settings.

It outlines areas of research in convention and CAM therapies, ways of integrating these therapies, development of curriculum that provides further education to health professionals, and an amendment of the Dietary Supplement Health and Education Act to improve quality, accurate labeling, research into use of supplements, incentives for privately funded research into their efficacy, and consumer protection against all potential hazards.

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